The invention relates to a class of compounds which have a structure related to naturally and synthetically occurring flavanoids and to pharmaceutical uses of the compounds.
The development of multiple drug resistance represents an increasing problem in cancer treatment. Within the past decade several mechanisms of drug resistance of tumor cells have been identified. One type of multiple resistance (MDR) has been shown to be mediated by an energy dependent, membrane-bound efflux pump termed P-glycoprotein (PGP) (Biochem. Biophys. Acta, 455, 152, 1976). PGP represents a member of the ATP-binding cassette with low substrate specificity (Nature, 323, 448, 1986). A broad range of cytostatic drugs such as anthracyclines, epipodyphyllotoxins, actinomycin D, vinca alkaloids, colchicines and taxol are eliminated via PGP-mediate efflux. Within the past few years a variety of substances have been shown to inhibit PGP-mediated drug efflux and thereby re-establish sensitivity toward chemotherapeutic agents (Pharmacol, Rev. 42, 155, 1990). These include ion channel blockers such as verapamil (Cancer Res. 41, 1967, 1981), amiodarone (Cancer Res 46, 825, 1986), propafenone (Proc. Am. Assoc. Cancer Res. 34, 321, 1993), dihydropyridines (Cancer Res. 43, 2267, 1983) phenothiazines (Mol. Pharmacol. 35, 105, 1989). Preliminary results obtained in clinical studies clearly demonstrate that modulation of MDR might be a successful approach in haematological malignancies, but serious side effects (cardiac effects, immuno-suppression and nephrotoxicity) often preclude optimal dosage of modulators (Cancer 72, 3553, 1993). Therefore, specifically designed highly active modulators with limited side effects are urgently required.
The present invention relates to a novel class of compounds which have structures related to certain naturally occurring and synthetic flavonoids and to pharmaceutical uses thereof.
Thus according to one aspect of the present invention, there is provided a compound of Formula (I):
Zxe2x80x94OCH2xe2x80x94Cxe2x89xa1CCH2xe2x80x94NRR1xe2x80x83xe2x80x83(I) 
or a pharmaceutically acceptable salt or solvate thereof wherein:
R and R1 are the same or different and each represents
lower C1-6 alkyl, or a carbocyclic group containing from 5 to 10 ring atoms, said ring atoms forming one or two rings wherein the or each ring contains 5 or 6 ring atoms, or
R and R1 taken together with the nitrogen atom to which they are attached, form a four- to eight-membered heterocyclic ring which may contain one or more additional heteroatoms selected from N, O or S, said heterocyclic ring being optionally substituted with a lower C1-4 alkyl group or a benzyl group;
Z represents: 
wherein
R2 and R3 are each independently selected from:
(i) hydrogen, (ii) a substituted or unsubstituted, preferably aromatic, carbocydic or heterocyclic group containing from 5 to 10 ring atoms, said ring atoms forming one or two rings wherein the or each ring contains 5 or 6 ring atoms, any heteroatoms being selected from N, O and S, any substituents being independently selected from the group consisting of
(a) Cl, (b) Br, (c) F, (d) OH, (e) NO2, (f) CF3, (g) C1-4 lower alkyl (in particular CH3), (h) SCH3, (i) NHCOCH3, (j) N(R6)(R8) wherein R6 and R8, are the same or different and each represents H or lower C1-4 alkyl, (k) OR10 wherein R10 represents H or lower C1-6 alkyl which may be saturated or unsaturated and being unsubstituted or substituted with the group NRR1 wherein R and R1 is as defined above, and (I) OCOR11 wherein R11 represents H or lower C1-4 alkyl,
(iii) Cl, (iv) Br, (v) F, (vi) OH, (vii) NO2, (viii) a saturated or unsaturated lower C1-6 straight or branched hydrocarbyl group which may be unsubstituted or substituted by 1, 2 or 3 substituents selected from Cl, Br, F, OMe, NO2 and CF3, (ix) NHCOCH3, (x) N(R6)(R8), (xi) SR10, (xii) OR10, and (xiii) OCOR11 wherein R6, R8, R10 and R11 are as defined above;
or
R2 and R3 taken together with the carbon atoms to which they are attached form a carbocyclic or heterocyclic ring having 5 or 6 ring atoms, any heteroatom being selected from N, O or S, said carbocyclic or heterocyclic ring being saturated or unsaturated, and being unsubstituted or substituted with one or more substituents selected from Cl, Br, F, OH, NO2, CF3, C1-4 lower alky, SCH3, NHCOCH3, N(R6)(R8), OR10 and OCOR11 wherein R6, R8, R10 and R11 are as defined above; and
R4 represents hydrogen, or OR10 wherein R10 is as defined above
or 
wherein R5 represents hydrogen or a lower C1-6 straight or branched hydrocarbyl group which may be unsubstituted or substituted by 1, 2 or 3 substituents selected from Cl, Br, F, OMe, NO2 and CF3.
Thus in one aspect the invention provides compounds having the structure (1Axe2x80x2): 
wherein
R2 and R3 are each independently selected from:
(i) hydrogen, (ii) a substituted or unsubstituted, preferably aromatic, carbocyclic or heterocyclic group containing from 5 to 10 ring atoms, said ring atoms forming one or two rings, wherein the or each ring contains 5 or 6 ring atoms, any heteroatoms being selected from N, O and S, any substituents being independently selected from the group consisting of:
Cl, Br, F, OH, NO2, CF3, C1-4 lower alkyl (in particular CH3), SCH3, NHCOCH3, N(R6)(R8), OR10 and OCOR11, wherein R6, R8, R10 and R11 are the same or different and each represents H or lower C1-4 alkyl,
(iii) Cl, (iv) Br, (v) F, (vi) OH, (vii) NO2, (viii) a saturated or unsaturated lower C1-6 straight or branched hydrocarbyl group which may be unsubstituted or substituted by 1, 2 or 3 substituents selected from Cl, Br, F, OMe, NO2 and CF3, (ix) NHCOCH3, (x) N(R6)(R8), (xi) SR10, (xii) OR10, and (xiii) OCOR11 wherein R6, R8, R10 and R11 are as defined above;
or
R2 and R3 taken together with the carbon atoms to which they are attached form a carbocyclic or heterocyclic ring having 5 or 6 ring atoms, any heteroatom being selected from N, O or S, said carbocyclic or heterocyclic ring being saturated or unsaturated, and being unsubstituted or substituted with one or more substituents selected from Cl, Br, F, OH, NO2, CF3, C1-4 lower alkyl, SCH3, NHCOCH3, N(R6)(R8), OR10 and OCOR11, wherein R6, R8, R10 and R11 are as defined above; and
R4 represents hydrogen, or OR10 wherein R10 is as defined above.
A preferred group of compounds are those wherein R, R1 and R4 are as defined for Formula (IAxe2x80x2) above, and
R2 and R3 are each independently selected from:
(i) hydrogen, (ii) a substituted or unsubstituted, preferably aromatic, carbocyclic or heterocyclic group containing from 5 to 10 ring atoms, said ring atoms forming one or two rings, wherein the or each ring contains 5 or 6 ring atoms, any heteroatoms being selected from N, O and S, any substituents being independently selected from the group consisting of:
(a) Cl, (b) Br, (c) F, (d) OH, (e) NO2, (f) CF3, (g) C1-4 lower alkyl (in particular CH3), (h) SCH3, (i) NHCOCH3, (j) N(R6)(R8) wherein R6 and R8, are the same or different and each represents H or lower C1-4 alkyl, (k) OR10 wherein R10 represents H or lower C1-6 alkyl which may be saturated or unsaturated and being unsubstituted or substituted with the group NRR1 wherein R and R1 is as defined above, and (I) OCOR11 wherein R11 represents H or lower C1-4 alkyl,
(iii) Cl, (iv) Br, (v) F, (vi) OH, (vii) NO2, (viii) a saturated or unsaturated lower C1-6 straight or branched hydrocarbyl group which may be unsubstituted or substituted by 1, 2 or 3 substituents selected from Cl, Br, F, OMe, NO2 and CF3, (ix) NHCOCH3, (x) N(R6)(R8), (xi) SR10, (xii) OR10, and (xiii) OCOR11 wherein R6, R8, R10 and R11 are as defined for Formula (I).
Within this group, R2 and R3 can both represent hydrogen. A further preferred group of compounds are those wherein one of R1 or R2 is hydrogen, and the other is selected from the group consisting of: (i) a substituted or unsubstituted, preferably aromatic, carbocyclic or heterocyclic group containing from 5 to 10 ring atoms, said ring atoms forming one or two rings, wherein the or each ring contains 5 or 6 ring atoms, any heteroatoms being selected from N, O and S, any substituents being independently selected from the group consisting of:
Cl, Br, F, OH, NO2, CF3, C1-4 lower alkyl (in particular CH3), SCH3, NHCOCH3, N(R6)(R8), OR10 and OCOR11, wherein R6, R8, R10 and R11 are the same or different and each represents H or lower C1-4 alkyl,
(ii) Cl, (iii) Br, (iv) F, (v) OH, (vi) NO2, (vii) a saturated or unsaturated lower C1-6 straight or branched hydrocarbyl group which may be unsubstituted or substituted by 1, 2 or 3 substituents selected from Cl, Br, F, OMe, NO2 and CF3, (viii) NHCOCH3, (ix) N(R6)(R8), (x) SR10, (xi) OR10, and (xii) OCOR11 wherein R6, R8, R10 and R11 are as defined for Formula (I).
Within this preferred group of compounds, a further preferred group of compounds are those wherein R2 hydrogen and R3 is selected from the group consisting of: (i) a substituted or unsubstituted, preferably aromatic, carbocyclic or heterocyclic group containing from 5 to 10 ring atoms, said ring atoms forming one or two rings, wherein the or each ring contains 5 or 6 ring atoms, any heteroatoms being selected from N, O and S, any substituents being independently selected from the group consisting of:
Cl, Br, F, OH, NO2, CF3, C1-4 lower alkyl (in particular CH3), SCH3, NHCOCH3, N(R6)(R8), OR10 and OCOR11, wherein R6, R8, R10 and R11 are the same or different and each represents H or lower C1-4 alkyl,
(ii) Cl, (iii) Br, (iv) F, (v) OH, (vi) NO2, (vii) a saturated or unsaturated lower C1-6 straight or branched hydrocarbyl group which may be unsubstituted or substituted by 1, 2 or 3 substituents selected from Cl, Br, F, OMe, NO2 and CF3, (viii) NHCOCH3, (ix) N(R6)(R8), (x) SR10, (xi) OR10, and (xii) OCOR11 wherein R6, R8, R10 and R11 are as defined for Formula (I).
A further preferred group of compounds are those wherein R3 is hydrogen and R2 is selected from the group consisting of: (i) a substituted or unsubstituted, preferably aromatic, carbocyclic or heterocyclic group containing from 5 to 10 ring atoms, said ring atoms forming one or two rings, wherein the or each ring contains 5 or 6 ring atoms, any heteroatoms being selected from N, O and S, any substituents being independently selected from the group consisting of.
Cl, Br, F, OH, NO2, CF3, C1-4 lower alkyl (in particular CH3), SCH3, NHCOCH3, N(R6)(R8), OR10 and OCOR11, wherein R6, R8, R10 and R11 are the same or different and each represents H or lower C1-4 alkyl,
(ii) Cl, (iii) Br, (iv) F, (v) OH, (vi) NO2, (vii) a saturated or unsaturated lower C1-6 straight or branched hydrocarbyl group which may be unsubstituted or substituted by 1, 2 or 3 substituents selected from Cl, Br, F, OMe, NO2 and CF3, (viii) NHCOCH3, (ix) N(R6)(R8), (x) SR10, (xi) OR10, and (xii) OCOR11 wherein R6, R8, R10 and R11 are as defined for Formula (I).
A further preferred embodiment of the present invention are compounds wherein R2 represents a substituted or unsubstituted, preferably aromatic, carbocyclic or heterocyclic group containing from 5 to 10 ring atoms, said ring atoms forming one or two rings, wherein the or each ring contains 5 or 6 ring atoms, any heteroatoms being selected from N, O and S, any substituents being independently selected from the group consisting of: Cl, Br, F, OH, NO2, CF3, C1-4 lower alkyl (in particular CH3), SCH3, NHCOCH3, N(R6)(R8), OR10 and OCOR11, wherein R6, R8, R10 and R11 are as defined as for Formula (I). For these compounds, R3 is preferably selected from the group consisting of H, Cl, Br, F, OH, NO2, a saturated or unsaturated lower C1-6 straight or branched hydrocarbyl group which may be unsubstituted or substituted by 1, 2 or 3 substituents selected from
Cl, Br, F, OMe, NO2 and CF3,
NHCOCH3, N(R6)(R8), SR10, OR10, and OCOR11 wherein R6, R8, R10 and R11 are as defined for Formula (I).
Alternatively compound R3 may represent a substituted or unsubstituted, preferably aromatic, carbocyclic or heterocyclic group containing from 5 to 10 ring atoms, said ring atoms forming one or two rings, wherein the or each ring contains 5 or 6 ring atoms, any heteroatoms being selected from N, O and S, any substituents being independently selected from the group consisting of:
Cl, Br, F, OH, NO2, CF3, C1-4 lower alkyl (in particular CH3), SCH3, NHCOCH3, N(R6)(R8), OR10 and OCOR11, wherein R6, R8, R10 and R11 are as defined for Formula (I).
For these compounds, R2 is preferably selected from the group consisting of H, Cl, Br, F, OH, NO2, a saturated or unsaturated lower C1-6 straight or branched hydrocarbyl group which may be unsubstituted or substituted by 1, 2 or 3 substituents selected from
Cl, Br, F, OMe, NO2 and CF3,
NHCOCH3, N(R6)(R8), SR10, OR10, and OCOR11 wherein R6, R8, R10 and R11 are as defined for Formula (I).
Where R2 and/or R3 represents a substituted carbocyclic or heterocyclic group, the substituents on the carbocyclic or heterocyclic group are preferably selected from OH or OR10 wherein R10 is as defined for Formula (I).
A particularly preferred carbocyclic group is phenyl or phenyl substituted with 1 to 3 OH or OR10 groups. For these compounds, R10 preferably represents methyl or 
Also preferred are compounds wherein one of R2 or R3 represents H or a lower C1-6 straight or branched hydrocarbyl group, with methyl being especially preferred.
The invention also provides a compound of Formula (I) having the structure (IAxe2x80x3): 
wherein R, R1 and R4 are as defined as for Formula (I), and R2 and R3 taken together represent Ring Q, said Ring Q being a carbocyclic or heterocyclic ring having 5 or 6 ring atoms, any heteroatom being selected from N, O or S, said carbocyclic or heterocyclic ring being saturated or unsaturated and being unsubstituted or substituted With one or more substituents selected from Cl, Br, F, OH, NO2, CF3; C1-4 lower alkyl, SCH3, NHCOCH3, N(R6)(R8), OR10 and OCOR11, wherein R6, R8, R10 and R11 are as defined as for Formula (I).
For these compounds Ring Q preferably represents a carbocyclic or heterocyclic aromatic ring, any heteroatom being selected from N, O or S, said ring being unsubstituted or substituted with one or more substituents selected from Cl, Br, F, OH, NO2, CF3, C1-4 lower alkyl, SCH3, NHCOCH3, N(R6)(R8), OR10 and OCOR11, wherein R6, R8, R10 and R11 are as defined as in Formula (I). Particularly preferred are those compounds wherein Ring Q represents a benzene or pyridine ring.
The substituent Z may be attached to any position in the aromatic ring. Thus the compounds of Formula (IAxe2x80x2) or (IAxe2x80x3) described above include compounds having the structures (IA)x, (IA)y and (IA)z: 
wherein R, R1, R2, R3 and R4 are as defined above.
For the compounds of Formula (IAxe2x80x2) or (IAxe2x80x3) described above, R4 preferably represents H, OH or OCH3.
The invention further provides compounds of Formula (I) having the structure (IB): 
wherein R and R1 are as defined for Formula (I) and R5 represents H or a lower C1-6 straight or branched hydrocarbyl group which may be unsubstituted or substituted by 1, 2 or 3 substituents selected from Cl, Br, F, OMe, NO2 and CF3. In a preferred embodiment, R5 represents H or methyl.
For the compounds of Formula (IB) described above, the substituent Z may be attached to any position in the aromatic ring. Thus the compounds of Formula (IB) described above include compounds having the structures (IB)w, (IB)x, (IB)y and (IB)z: 
wherein R, R1 and R5 are as defined for Formula (I).
For the compounds of Formulae (I), (IAxe2x80x2), (IAxe2x80x3) or (IB), the substituent R and R1 are the same or different and preferably each represents a C1-4 alkyl group or a C5-8 cycloalkyl group. Within this group of compounds, R and R1 are preferably independently selected from methyl, ethyl, propyl, cyclopropyl or a cyclohexyl group.
In a preferred group of compounds, the R and R1 groups taken together with the nitrogen atom to which they are attached, form a four- to eight-membered heterocyclic ring. Of these, it is preferred that R and R1 taken together with the nitrogen atom to which they are attached, form a pyrrolidine, piperidine, piperazine, N-methylpiperazine, N-benzylpiperazine or a morpholine group.
It will be appreciated that the compounds of Formula (I) contain a basic amino function and thus may be converted to acid addition salts, with pharmacologically acceptable acids, e.g. hydrochloric acid and phosphoric acid. Such salts are also included in the present invention.
The compounds of Formula (I) may be conveniently prepared by a process comprising the steps of:
(i) reacting a hydroxy derivative, Zxe2x80x94OH, with propargyl bromide to form an alkyne, Zxe2x80x94OCH2Cxe2x89xa1H; and
(ii) reacting the alkyne Zxe2x80x94OCH2Cxe2x89xa1H with an amine HNRR1. Such a process forms a further aspect of the present invention.
The invention further provides a compound of Formula (I) as defined above for use as a modulator of multiple drug resistance in cancer chemotherapy or an antiproliferative medicament. In particular, the compounds of Formula (I) are especially useful for the modulation of multiple drug resistance mediated by P-glycoprotein.
The compounds of Formula (I) as defined above may also be useful for the manufacture of a medicament for the treatment or prevention of neoplasms, particularly those located in the uterus, ovary or breast. Further the compounds Formula (I) may be especially useful for the manufacture of a medicament for the treatment of paclitaxel- and docetaxel-resistant cancer cells.
The compounds of Formula (I) may also advantageously be used as an antiproliferative medicament in combination therapies involving the combined use of a compound of Formula (I) with one or more anti-neoplastic or cytostatic agents, such as paclitaxel or docetaxel. The combination therapy may involve simultaneous or successive administration of a compound of Formula (I) with one or more antineoplastic or cytostatic agents, including anthracyclines, epipodophyllotoxins, actinomycin D, vinca alkaloids, colchicines, paclitaxel or docetaxel. Such combination therapy forms a further aspect of the invention.
The compounds of the invention may also be useful in the manufacture of a medicament for the treatment or prevention of menopausal disorders and osteoporosis.
The invention further provides a pharmaceutical composition comprising one of more of the compounds of Formula (I) in combination with one or more pharmaceutically acceptable excipients. Such a composition may also comprise one or more antineoplastic or cytostatic agents, such as paclitaxel or docetaxel.
The invention will now be described by way of illustrative examples and with reference to the accompanying formulae drawings.